T helper 2 (Th2) effector cells, through their production of specific cytokines, play an important role in mediating resistance to helminthic parasite infection. Understanding the cell and molecular interactions that lead to their differentiation is therefore important for the development of therapies and vaccines that promote host protective immune responses. In this proposal, we will continue to investigate Th2 effector cell development during primary and memory responses to nematode parasites. For the primary response, we will utilize an Ag-specific model system that we have adapted to study the differentiation of naive CD4 T cells into highly polarized Th2 effector cells in vivo. Because these Ag-specific CD4 T cells recognize an unrelated nonparasite Ag, we can focus on cell populations and specific molecules associated with nematode infection, which may promote Th2 cell development independently of the specific peptide Ag recognized by the T cell receptor. Because the peptide that the Ag-specific T cell recognizes is separate from the parasite, we can differentiate the effects of peptide Ag dose, recognized by the TCR, from the dose of nematode parasites and its associated structures, which may influence the course of the Th2 immune response through nonAg-specific mechanisms. We will use this model system to examine the role of extrinsic factors including peptide Ag dose, IL-4, B cells, and specific lymph node dendritic cell populations in regulating Th2 effector cell development from naive CD4 T cells. We will also use this model system to try to develop a soluble extract from nematode parasites that can promote in vivo Th2 cell differentiation by functioning as a microbial adjuvant. For the memory response, we will focus on peripheral memory Th2 effector cell migration and function using both the Ag-specific model system and the natural infection. We have recently determined that CD4 + Th2 cells encircle developing larvae in the submucosa during, the host protective memory response, but not the primary, chronic response to Heligmosomoides polygyrus. We will examine whether this localized response at the host:parasite interface damages developing larvae and contributes to host protection and we will investigate the chemokines mediating CD4 Th2 memory cell migration to tertiary sites of infection. In parallel studies, we will use the Ag-specific T cell model system to investigate the chemokines mediating CD4 Th2 memory cell migration to tertiary tissue sites. These latter studies should provide useful insights into mechanisms of peripheral memory Th2 cell localization and function during parasite infection.